1-phenyl-3-(4-phenyl-1-piperazinoalkyl)-imidazolidinones and imidazolidinethiones



United States Patent ABSTRACT OF THE DISCLOSURE The preparation of imidazolidinones and imidazolidinethiones having a phenyl or substituted phenyl group in the 1-position and 4-phenyl or substituted phenyl-l-piperazinyl lower alkylene' groups in the 3-position. The phenyl groups may have substituents such as halogen, lower alkyl, lower alkoxy or trifiuoromethyl present. These compounds are useful as tranquilizers.

In the past, imidazolidinones and imidazolidinethiones have been described which have aryl groups on one or both of the nitrogen atoms, however, none have been found which contain an aryl group on one nitrogen and a (4-phenyl-1-piperazinyl)alkyl group on the other nitrogen of the heterocyclic basic ring structure.

We have now found that compounds which have the following structure are highly active physiologically:

4 R Ra r Qt 1 2 wherein R, R R and R are selected from the group consisting of hydrogen, halogen, lower alkyl, lower. alkoxy and trifiuoromethyl, R A and B are selected from the group consisting of hydrogen and lower alkyl, Y is selected from the group consisting of oxygen and sulfur, n is an integer from 2 to 4 and pharmaceutically acceptable ,acid addition salts of the above compounds.

The compounds of the present invention may be solids or liquids at room. temperature in the form of their free bases. As such, they are relatively insoluble in water but are soluble in or miscible with most organic solvents such as, for example, lower alkyl alcohols, esters, acetone, chloroform and the like. These compounds form acid addition salts with strong acidssuch as hydrochloric acid, sulfuric acid, perchloric acid and the like. These salts are, in general, soluble in water, methanol, ethanol, etc. but relatively insoluble in benzene, ether, petroleum-ether and the like.

The resent compounds have been found to have tranquilizing properties which show a desirable therapeutic index i.e., wide-spread between the doses producing sedative action and toxic symptoms such as paralysis or lethality.

The compounds of this invention may be prepared by the following method which has been found most desirable R1 H R:

3,374,237 Patented Mar. 19, 1968 wherein R, R R R R A, B and n are as defined above and X is a reactive halogen or arylsulfonyloxy radical. The substituted imidazolidinone starting material is dis-- solved in an inert solvent such as, for example, dimethylene glycol dimethyl ether (diglyme) and reacted with a condensing agent such as sodium hydride and then withan appropriate aminoalkyl halide. The reaction is best carried out at temperatures in the range of 30-200 C. for a period of from 30 minutes to 4 hours. The product can be recovered by methods well known in the art and described hereinafter in the examples 7 V l The compounds of the present invention can also be prepared by several other methods, one group of which have in common the cyclization of a straight 'chaincornpound to produce the desired imidazolidinone ring stru'cture with the substituents present thereof. One method, found useful in producing the compounds of the present invention is the cyclization of substituted carbanilates which can be illustrated by the following reaction. 2. V

- ll R R4 ooon15 R h R A B R3 wherein R, R R R R A, B and n are as defined above hereinbefore.

The present compounds can also be prepared by the cyclization of N-substituted (aminoalkyl) ureas. This reaction can be illustrated as follows: I

R1 A B R:

in which R, R R R R A, B and n are as defined hereinbefore. The starting material, namely, N-(s'ubstituted aminoalkyDureas can be prepared by the various methods described in the chemical literature.

Other methods of preparing the compounds of the radical. The reaction conditions do not appear to be presentinventioncan be illustrated as follows: critical. The alkylating agent (containing X) is reacted O with the amine in excess or in the presence of an acid B4 II acceptor such as sodium or potassium carbonate, sodium R 5 hydroxide, pyridine and the like. The reaction is prefer- Q-N N'CnHh-N-CHCHNII ably carried out in the presence of an excess of the amine I I or in a solvent such as benzene toluene ethanol acetone R] A B R: a 3

A B and the like. The reaction is best carried out within the R4 range of about 20 C. to about 150 C. for a period from R l l R about 30 minutes to several hours. The product can be @N C..H1n-N N-Q recovered by methods well known in the art and as de- El C scribed hereinafter in the examples.

9, The corresponding imidazolidinethiones are also a part of this invention and in some cases they can be prepared 5. v R Ii by procesfses 1silmilar to those Idescribed above. 1;: is, howi 4 ever, pre era e to prepare t ese compounds y specia R -l R3 procedures, such as by the reaction of the imidazolidinone Q 2 with phosphorous pentasulfide as described hereinafter in U the examples.

A B The products of the present invention as tranquilizers R R4 R can be incorporated in various pharmaceutical forms such -I 3 as tablets, capsules, pills and so forth, for immediate or N n znsustained release, by combining with suitable carriers. R1 fi They may be in the form of dosage units for a single 0 therapeutic dose or in small units for multiple dosages or in larger units for division into single doses. Obviously, in Whlch R, 1 2 3 4 A, B and n are as defined in addition to the therapeutic trauquilizing compound above. there may be present excipients, binders, fillers and other The various cyclization reactions illustrated above can therapeutically inert ingredients necessary in the fo l be carried out, for example, by heating the reagents alone ti f the desired Pharmaceutical preparation or in the presence of a solvent inert to the reactants at The follo i ifi examples illustrate h preparaa temperature within the range of about 100 C. to about tion f representative 1- 1-3- (4 1 p i i for a Period of from about 30 minutes to about alkyl]-2-i-midazolidinones and imidazolidinethiones of the 10 hourspresent invention. Parts are by weight unless otherwise Further methods of preparing the compounds of the indicated, present invention can be used, such as, the reaction of XAMPL 1 N (substituted aminoalkylene)-N'-arylalkylenediamines with cyclizing agents such as ethyl chloroformate, phosgene, ethyl carbonate and the like. The preparation of Preparation of l-(m-chlorophenyl)-3-[2-(4-phenyl-1- piperazinyl)-ethyl]-2-imidazolidfnone dihydrochlothe present compounds by this latter method can be il- 40 ride lustrated as follows: A solution of 5.7 parts of l-(m-chlorophenyl)-2-imid- 6. R R o N N-CnH:n-NH(i7H(I3H-NH oi-ii-oi R; A B B2 A B R R 3 -N No.,1-n..-N N@ 1 g R:

in which R, R R R R A, B and n are as defined hereinbefore.

A still further method for preparing compounds of the azohdmone m 100 parts of dlglynie 15 p i present invention can be illustrated as follows: to a slurry of parts of 50% sodmm hydnde (m eral oil) in 25 parts of diglyme. The react-ion mixture is stirred for one hour, and a solution of 8.0 parts of l-(2-ch1oroethyl)-4-pheny1piperazine in 50 parts of ether R a is added. The reaction mixture is heated so as to grad- 5 G ually distill ofi the ether and then heated at reflux tem- R R perature for 3 hours. After cooling, the precipitate is filll tered off, and the mother liquor is concentrated to remove the solvent. The residue is shaken with a mixture A B of benzene and dilute hydrochloric acid and the benzene layer is separated and discarded. The aqueous layer is R4 R R3 treated with an excess of sodium hydroxide and extracted N C,,H n-N N 4-H with benzene. The benzene layer is concentrated to a R] R o waxy residue, which is triturated with hexane and then P filtered. 0n recrystallization from benzene and hexane l (m-chlorophenyl) 3 [2 (4-phenyl-1-piperazinyl) ethyl]-2-imidazolidinone, melting point 151 152 C., is wherein R, R R R R A, B and n are as defined obtained. The base is converted to the dihydrochloride, above and X is a reactive halogen or arylsulfonyloxy melting point 213-214 C.

5 EXAMPLE 2 Preparation of J-(m-bromophenyl)-3-[2-(4-phenyl- I-piperazinyl)-ethyl]-2-imidazolidinone The above compound is obtained when l-(m-bromophenyl)-2-imidazolidinone is substituted for l-(m-chlorophenyl)-2-imidazolidinone in the procedure of Example 1.

EXAMPLE 3 Preparation of 1- (3-chloro-4-methylphenyl) -3- [2- (4- phenyl-I-piperazinyl) ethyl]-2-imidazolidinone When the procedure of Example 1 is followed and 1-(3-chloro-4-methylphenyl)-2-imidazolidinone is substituted for 1 (m-chlorophenyl)- 2 -imidazolidinone, the above compound is obtained.

EXAMPLE 4 Preparation of 1-(m-methoxyphenyl-)3-[2-(4-phenyl- I-piperazinyl) ethyl] -2-imidazolidinone The above compound, melting point 11=9120 C., is obtained when l-(m-methoxyphenyl)-2-imidazolidinone is substituted for 1-(m-chlorophenyl)-2-imidazolidinone in the presence of Example 1.

EXAMPLE 5 Preparation of J-(m-chlorophenyl)-4-methyl-3-[4-(4 phenyl-I-piperazinyl) batyl1-2-imidazolidinone This compound is obtained when 1-(m-chlor0phenyl)- 4-methyl-Z-imidazolidinone is reacted with 1-(4-chlorobutyl)-4-phenylpiperazine as described in Example 1.

EXAMPLE 6 Preparation f 3- p-fluorophenyl -4-methyl-1 [3- (4 pheny l-1 -piperazinyl propyl -2-imidazolid inane The above compound is formed when I-(p-fluorophenyl)--methyl-2-imidazolidinone is reacted with 1-(3-chloropropyl)-4-phenyl piperazine by the procedure described in Example 1.

EXAMPLE 7 Preparation of 1-(m-trifloromethylphenyl)-3-[2-(4- phenyl-l-piperazinyl) ethyl] -2-imidazolidinone Preparation of 1 3,5 -dichlorophenyl -3 [2- (4 -phen-y ll-piperazinyl) ethyl] -2-imidazolidinone This compound is obtained when 1-(3,5-dlchlorophenyl)-2imidazolidinone is substituted for l-(m-chlorophenyl)-2-imidazolidinone in the process of Example 1.

EXAMPLE 9 Preparation of l-(m-chlorophenyl)-3-[3-(4-phenyl-1- piperazinyl)propyl]-2-imidazolidinone hydrochloride A solution of 37 parts of l-(m-chlorophenyl)-2-i-midazolidinone in 250 parts of diglyme is added to a suspension of 11.5 parts of 50% sodium hydride (in mineral oil) in 1 00 parts of diglyme and the mixture is stirred for one hour. The reaction mixture is cooled, 38 parts of 1,3-dibromopropane is added and the mixture is stirred at room temperature for 18 hours. The solid is filtered oh and the mother liquor is concentrated to remove the solvent. The residue is l-(3-bromopropyl)-3-( m-chlorophenyl -2-imidazolidinone.

A mixture of 23 parts of l-phenylpiperazine and 15.2 parts of 1-(3brornopropyl) 3 (m-chlorophenyD-2-imidazolidinone in 50 parts of benzene is heated at reflux temperature overnight. One hundred parts of benzene is added and the mixture is extracted with sodium carbonate solution and then with Water. The benzene layer is extracted with 80 parts of 5 N hydrochloric acid. The aqueous layer is made alkaline with 100 parts of 5 N sodium hydroxide solution and extracted with ether. The other layer is concentrated and the residue is triturated with hexane and then with ether. The crystalline product, melting point 111-l13 C., is warmed with ethanolic hydrogen chloride until solution occurs. On cooling, l-(m-chlorophenyl) 3 [3-(4-phenyl-l-piperazinyl) propyl]-2-imidazolidinone hydrochloride precipitates. The melting point after recrystallization again forms ethanol EXAMPLE 10 Preparation of I-(m-chlorophenyl) 3 [3-[4-(m-chlor0- phenyl)-1-piperazinyl]propyl] 2 imidazolidinone hydrochloride This compound, melting point 207209 C., is obtained when 1-(m-chlorophenyl)piperazine is substituted for 1- phenylpiperazine in the procedure of Example 9.

EXAMPLE 11 Preparation of 1 (m-chlorophenyl -3- [3 [4- (p-methoxypenyl) -1-piperazinyl] propyl] -2-imidazolidin0ne When 1-(p-methoxpheuyl)piperazine is substituted for l-phenylpiperazine in the procedure of Example 9, the above compound is obtained having a melting point of 114115 C.

EXAMPLE 12 Preparation of 1 (m-chlor0phenyl)-3- [3- [4-(m-trifluoromethylphenyl) -1-piperazinyl]pr0pyl] -2-imidaz0lidinone If 1-(m-trifluoromethylphenyl)piperazine is substituted for l-phenylpiperazine in the procedure of Example 9, this compound is isolated.

EXAMPLE 13 Preparation of I-(m-chlorophenyl)-3-[3-[4-(p-fluorophenyl)-1-piperazinyl1pr0pyl]-2imidaz0lidinone This compound is obtained when l-(p-fiuorophenyl) piperazine is substituted for l-phenylpiperazine in the procedure of Example 9.

EXAMPLE 14 Preparation of 1-(rn-chl0r0phenyl)-3-[3-[4-(m-tolyl) 1 -piperazinyl] propyl] -2-imidaz0lidinone The above compound is obtained when l-(rn-tolyl) piperazine is substituted for l-phenylpiperazine in the process of Example 9.

Preparation of 1-(m-chl0r0phenyl)-3[3-[4:(p-chloropenyl)-1-piperazinyl]propyl]-2-imidazolldinone The above compound, melting point 154-156 C., is obtained when l-(p-chlorophenyl)piperazine is substituted for l-phenylpiperazine in the procedure of Example 9.

EXAMPLE 17 Preparation of 1 -phenyl-3- [3- (4-phenyl-1 -piperazinyl) propyl]-2-imidazolidinone hydrochloride A mixture of 2.5 parts of l-(m-chlorophenyl)-3-[3 (4-phenyl-1-piperaziny1)propyl] 2 imidazolidinone hydrochloride (Example 8), 100 parts of ethanol and 1 part of 10% palladium-on-carbon catalyst is shaken in a Parr hydrogenator under about three atmospheres of hydrogen pressure until reduction is complete. The catalyst is filtered off and the mother liquor is concentrated. The

7 residue is triturated with 3 parts of 2.5 N ethanolic hydrochloric acid and 50 parts of ether. The crystalline product is filtered off and recrystallized from ethanol, melting point 241243 C.

EXAMPLE l8 Praparation f 1 -phenyl-3 [3 (4-phenyl-1 -piperazinyl) propyl] -2-imidazolidinethione A mixture of 25 parts of 1-phenyl-3-[3-(4-phenyl-lpiperazinyl)propyl]-2-imidazolidinone, 25 parts of phosphorous pentasulfide, and 100 parts of xylene is heated in an oil bath at 155 -160 C. for 28 hours. After cooling, a mixture of 350 parts of 2 N sodium hydroxide solution and 200 parts of benzene is added. The mixture is warmed slightly to dissolve the gummy product and the layers are separated. The organic layers are washed with water and the desired product is then extracted into 250 parts of 1 N hydrochloric acid. The aqueous layer is made alkaline with 60 parts of 5 N sodium hydroxide and extracted with ether. The l-phenyl 3 [3 (4-phenyl-1-piperazinyl) propyl]-2-imidazolidinethione is recovered by concentration of the-ether layer.

EXAMPLE 19 Preparation of I-(m-chlorophenyl)-3-[3-[4-(3,5-dichlorophenyl) -1-pipcrazinyl]propyl] -2-imidaz0lidin0ne The above compound is obtained when 1-(3,5-cli chlorophenyl)piperazine is used in place of l-phenylpiperazine in the procedure of Example 9.

EXAMPLE 20 Preparation of I-(m-chlorophenyl)-3-[3-(3-methyl-4- phenyl-l-piperazinyl propyl] -2-imidaz0lidinone This compound is obtained when 2-methyl-1-phenylpiperazine is substituted for l-phenylpiperazine in the procedure of Example 9.

We claim:

1. A member selected from the group consisting of compounds of the formula:

and trifluoromethyl, R A and B are selected from the group consisting of hydrogen and lower alkyl groups, Y

is selected from the group consisting of oxygen and sulfur, n is an integer from 2 to 4 and pharmaceutically acceptable acid addition salts of said compounds.

2. The compound 1-(m-chlorophenyl)-3-[2-(4-phenyll-piperazinyl ethyl] -2-irnidaz0lidinone.

3. The compound l-(m-brornophenyl)-3-[2-(4-phenyll-pip erazinyl ethyl] -2-imid azolidinone.

4. The compound 1-(3-chloro-4-methylphenyl)-3-[2- (4-phenyl 1 piperazinyl)ethyl]-2-imidazolidinone.

5. The compound l-(m-methoxphenyl) 3 [2-(4- phenyl-l-piperazinyl ethyl] -2-imidazolidinone.

6. The compound 1-(m-chlorophenyl)-4-methyl-3-[4- (4-phenyl-1-piperazinyl)butyl] -2-irnidazolidinone.

7. The compound 3-(p-fluorophenyl)-4-methyl-1-[3- (4-phenyl-1-piperazinyl)propyl] -2-imidazolidinone.

8. The compound 1-(m-trifluoromethylphenyl)-3-[2- (4-phenyl-1-piperazinyl) ethyl] -2-imidazolidinone.

9. The compound 1-(3,5-dichlorophenyl 3 [2-(4- phenyll-piperazinyl ethyl] -2-imidazolidinone.

10. The compound l-(m-chlorophenyl) 3 [3-(4- phenyl-1-piperazinyl)propyl] -2-imidazolidinone.

11. The compound 1-(m-chlorophenyl)-3-[3-[4-(mchlorophenyl -1-piperazinyl propyl] -2-irnidazo1idinone.

12. The compound l-(m-chlorophenyl)-3-[3-[4-(pmethoxyphenyl 1-piperazinyl1propy1] -2-imid azolidinone.

13. The compound 1-(m-chlorophenyl)-3-[3-[4-(mtrifluoromethylphenyl)-1-piperazinyl]propyl] 2 imidazolidinone.

14. The compound l-(m-chlorophenyl) 3 [3-[4-(pfiuorophenyl) -1-piperazinyl] propyl] -2-imidaz01idinone.

15. The compound 1-(m-chloropheny1)-3-[3-[4-(mtolyl) -1-piperazinyl]propyl] -2-imidazolidinone.

16. The compound 1-(m-chlorophenyl)-3-[3-[4-(mbromophenyl -1-piperazinyl] propyl] -2-imidazolidinone.

17. The compound 1-phenyl-3-[3-(4-phenyl-1-piperazinyl propyl] -2-imid azolidinone.

18. The compound 1-phenyl-3-[3-(4-phenyl-l-piperazinyl)propyl]-2-imidazolidinethione.

19. The compound 1-(m-chl0rophenyl)-3-[3-[4-(pchlorophenyl -1-piperzinyl] propyl] -2-imidazolidinone.

OTHER REFERENCES Elderfield: Heterocyclic Compounds, vol. 5 (19), pp. 250 251.

HENRY R. JILES, Primary Examiner. 

